Project Summary/Abstract Phenols are chemicals found in numerous everyday items ranging from personal care products to food packaging materials. Exposure is widespread, with detectable urinary levels in populations worldwide. Studies have shown that phenols can act as endocrine disruptors, with estrogenic, antiestrogenic, and antiandrogenic effects. They also impact drug metabolizing enzymes which mediate the body?s detoxification processes, and hormone metabolism and bioavailability underlying normal reproductive function. Despite plausible mechanisms by which phenols could impact female reproductive function, there are inconsistent results across the limited epidemiologic studies examining the reproductive effects of phenol exposure. In part, this is because phenols are rapidly metabolized and excreted, making exposure assessment challenging. To accurately characterize phenol exposure, repeated measures are necessary, but most studies to-date use a single measure. This proposal leverages questionnaire and diary data, along with repeated daily urine samples, from a prospective cohort of 221 women attempting pregnancy, the Early Pregnancy Study. It aims to examine the relationship between exposure to five phenols (benzophenone-3, methyl paraben, propyl paraben, 2,4-dichlorophenol, and 2,5-dichlorophenol) and a range of reproductive function indicators, and to investigate potential phenol-associated changes in drug metabolizing enzymes, and hence hormone metabolism, through assessment of the urinary metabolome. Aim 1 evaluates whether concentrations of phenols are associated with reproductive function. We will quantify the associations between phenol levels and time to pregnancy, risk of early pregnancy loss, follicular phase length, and hormone levels. In Aim 2, we investigate potential pathways by which phenols may have endocrine disrupting effects and alter the urinary metabolome using both targeted and untargeted metabolomics approaches. By integrating preconception epidemiologic, biomarker, and metabolomics data with fertility outcomes, this study will offer an exposome-level view into how reproductive function may be affected by environmental exposures. Because infertility is a growing public health concern with major physical, emotional, and financial consequences, the identification of reproductive toxicants is urgently needed. If phenols contribute to decreased fertility, then minimizing the preconception use of common phenol-containing consumer products could have substantial public health benefits. Completion of this two-year research and training fellowship will provide the applicant with the opportunity to develop advanced data analysis and interpretation skills in both metabolomics and epidemiology. During this fellowship, a multi-disciplinary team of mentors at the Yale School of Public Health and NIEHS will work with the applicant towards her long-term goal of conducting scientific research in reproductive and environmental health, and mentor and train environmental health students.